Neoplasms, Neoplasm Metastasis, Pancreatic Cancer
Conditions
Keywords
Neoplasms, Neoplasm Metastasis, Pancreatic Cancer
Brief summary
Phase 1b: To determine the safe and tolerable dose of galunisertib in combination with gemcitabine in patients with solid malignancy Phase 2a: To compare the overall survival (OS) of patients with Stage II to IV unresectable pancreatic cancer when treated with a combination of galunisertib and gemcitabine with that of gemcitabine plus placebo.
Interventions
DRUGGalunisertib
Administered orally
DRUGGemcitabine
Administered intravenously
DRUGPlacebo
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
For both Phase 1b and Phase 2 (unless specified in the following), patients are eligible to be included in the study only if they meet all of the following criteria: For Phase 1b: * Have histological or cytological evidence of a diagnosis of cancer that is advanced and/or metastatic disease; that is refractory to standard therapy and/or therapies known to provide clinical benefit or for which no standard therapy exists; and/or in which gemcitabine therapy at the proposed doses and schedule would be considered appropriate treatment for the metastatic disease (eg, pancreatic cancer) * Patients may have received prior chemotherapy, radiotherapy, cancer-related hormone therapy, or other investigational therapy as treatment. There is no limit in the number of previous lines of therapy. For Phase 1b and Phase 2: * Have measurable disease or non-measurable disease, defined according to Response Evaluation Criteria In Solid Tumors (RECIST) * Have given written informed consent prior to any study-specific procedures * Have adequate organ function including: Hematologic: absolute neutrophil count (ANC) greater than or equal to 1.5 x 10\^9/L, platelets greater than or equal to 100 x 10\^9/L, and hemoglobin greater than or equal to 9 g/dL. Hepatic: bilirubin less than or equal to 1.5 times upper limit of normal (ULN), and alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT)less than or equal to 2.5 times ULN. If the liver has tumor involvement, AST less than or equal to 5 times ULN and ALT less than or equal to 5 times ULN are acceptable. Patients may have endoscopic or radiologic stenting to treat biliary obstructions. If so, then bilirubin must return to less than or equal to 1.5 times ULN and ALP, AST, and ALT to less than or equal to 5 times ULN prior to enrollment. Renal: serum creatinine within normal limits, less than or equal to 1.5 times ULN. * Have a performance status of less than or equal to 2 on the Eastern Cooperative Oncology Group (ECOG) scale * Patients must have recovered from any Grade 3/4 toxicities of previous therapies * Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures * Prior radiation therapy for treatment of cancer is allowed to \<25% of the bone marrow, and patients must have recovered from the acute toxic effects of their treatment prior to study enrollment. Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 4 weeks before study entry. * Male and female patients with reproductive potential must use an approved contraceptive method during and for 3 months after discontinuation of study treatment. Women of childbearing potential must have a negative beta-human chorionic gonadotropin (B-HCG) pregnancy test documented within 14 days prior to treatment. If condoms are used as a barrier contraceptive, a spermicidal agent should be added to ensure that pregnancy does not occur. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. For Phase 2: * Have histological or cytological diagnosis of adenocarcinoma of the pancreas that is locally advanced (Stage II, III) or metastatic (Stage IV) and not amenable to resection with curative intent. Patients with previous radical surgery for pancreatic cancer are eligible after progression is documented. If they received adjuvant chemotherapy or chemoradiotherapy with gemcitabine, they can be enrolled if the treatment was completed 3 months before or longer * Tumor tissue or unstained slides are available from original biopsy or resection or other tumor biopsies * Patients may have received previous adjuvant treatment with gemcitabine with or without radiotherapy for pancreatic cancer. Adjuvant treatment must have finished at least 6 months before enrolling.
Exclusion criteria
Patients will be excluded from the study if they meet any of the following criteria: * Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or unapproved use of a drug or device (other than the investigational product used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study * Have moderate or severe cardiac disease: * Myocardial infarction within 6 months prior to study entry, unstable angina pectoris, New York Heart Association (NYHA) Class III/IV congestive heart failure, or uncontrolled hypertension * Major abnormalities documented by echocardiography with Doppler (for example, moderate or severe heart valve function defect and/or left ventricular ejection fraction (LVEF) \<50%, evaluation based on the institutional lower limit of normal) * Predisposing conditions that are consistent with development of aneurysms of the ascending aorta or aortic stress (for example, family history of aneurysms, Marfan-Syndrome, bicuspid aortic valve, evidence of damage to the large vessels of the heart documented by CT scan or MRI with contrast) * Are unable to swallow tablets or capsules * Are pregnant or breastfeeding * Have any significant medical illnesses that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy * Have a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ), unless in complete remission and off of all therapy for that disease for a minimum of 3 years * Have active infection that would interfere with the study objectives or influence study compliance * Phase 2 only: Endocrine pancreatic tumors or ampullary cancer * Patients with acute or chronic leukemia or with any other disease likely to have a significant bone marrow infiltration (screening not required) * Have previously completed or withdrawn from this study or any other study investigating galunisertib or any other TGF-ß inhibitor * Have known allergy to galunisertib or gemcitabine or any ingredient of galunisertib or gemcitabine formulations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Recommended Phase 2 Dose | Time of first phase 1b dose until time of last phase 1b dose (up to 1 year) | The recommended Phase 2 dose was the highest dose where less than 1/3 of participants experienced dose limiting toxicities (DLTs). The recommended dose was determined based on a review of overall toxicity, dose reductions, omissions, and pharmacokinetic information from Phase 1b. |
| Phase 2: Overall Survival (OS) | Baseline to date of death from any cause (up to 2 years) | Overall survival is defined as the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date for a particular analysis, overall survival duration was censored for that analysis at the date of last prior contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants With Tumor Response | Baseline to end of Phase 1b (up to 1 year) | Response was defined using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Complete Response (CR) was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeter (mm) and normalization of tumor marker level of non-target lesions; Partial Response (PR) was defined as having at least a 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD) was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir; Stable Disease (SD) was defined as small changes that did not meet above criteria. |
| Phase 2: Progression Free Survival (PFS) | Baseline to first date of progressive disease or death due to any cause (up to 2 years) | PFS is defined as the date of randomization to the first date of progression of disease or of death from any cause. For each participant who is not known to have died or to have had a progression of disease as of the data-inclusion cut-off date for a particular analysis, PFS will be censored at the date of last prior contact. PFS will be calculated and analyzed twice: (1) including clinical progressions of disease not based on lesion measurements, and (2) excluding clinical progressions. Progression Disease (PD) was defined as having at least a 25% increase in the sum of the longest diameter of target lesions. |
| Phase 2: Percentage Change From Baseline in Tumor Size (CTS) | Baseline, end of Cycle 2 (up to 56 days) | Change in tumor size is defined as the maximum percent change from baseline in the sum of target lesions. Change was assessed in each participant using radiographic imaging. |
| Phase 2: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR]) | Baseline to measured progressive disease (up to 2 years) | Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the independent central review according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100. |
| Phase 1b: Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 24 Hours (AUC[0-24], ss) and Time Zero to Infinity (AUC[0-∞], ss) | Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16) | AUC\[0-24h\] is a combined measure obtained from Day 14 at 0 hour (pre-dose), 0.5, 2,3, 6 hours post dose and morning doses from 24h and 48h to compute. AUC0-infinity will take 48h and extrapolation beyond this in addition to earlier time points to be calculated. All mentioned time points are used to calculate the two AUCs. |
| Phase 2: Population PK: Maximum Concentration (Cmax) of Galunisertib | Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16) | Plasma samples for pharmacokinetic (PK) analysis were obtained on Day 14 at 0 hours (Pre-dose), 0.5, 2, 3, 6 hours post dose and morning doses from 24h and 48h. Cmax takes all time points post dose into account and one value is reported. |
| Phase 2: Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) at Study Completion | Baseline, study treatment completion (up to 1 year) | The BPI-SF Pain Severity Subscale was a participant-rated questionnaire that measured the severity of pain. Severity scores could have ranged from 0 (no pain) to 10 (pain as bad as you can imagine) for questions that included assessing average pain in the past 24 hours. |
| Phase 2: Change From Baseline in Carbohydrate Antigen 19.9 (CA19-9) Level at First Study Completion Follow-up | Baseline, study treatment completion after first follow up visit (up to 1 year) | Carbohydrate antigen 19-9 (CA 19-9) is a modified Lewis(a) blood group antigen, and has been used as a tumor marker. The outcome measure is the median, minimum and maximum values from participants who had samples collected at baseline and at follow-up |
| Phase 2: Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) | Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16) | AUC\[0-24\] is a combined measure obtained from Day 14 at 0 hour (pre-dose), 0.5, 2,3, 6 hours post dose and morning doses from 24h and 48h to compute. |
| Phase 1b: Pharmacokinetics: Maximum Plasma Drug Concentration at Steady State (Cmax,ss) | Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16) | Plasma samples for pharmacokinetic (PK) analysis were obtained on Day 14 at 0 hours (Pre-dose), 0.5, 2, 3, 6 hours post dose and morning doses from 24h and 48h. Cmax takes all time points post dose into account and one value is reported. |
Countries
Belgium, France, Germany, Italy, Spain, United States
Participant flow
Pre-assignment details
Completers included participants who died from any cause and participants who were alive and on study (either on study treatment or in long term follow-up) at study conclusion.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: 80 mg Galunisertib + Gemcitabine Cohort 1: 40 mg Galunisertib was administered orally twice daily (BID) for 14 days followed by 14 days of rest (28 day cycle).
Gemcitabine at a dose of 1000 mg/m\^2 was administered intravenously once per week for 7 weeks followed by 1 week of rest and then once per week for 3 weeks of every 4 weeks. | 5 |
| Phase 1b: 160 mg Galunisertib + Gemcitabine Cohort 2: 80 mg Galunisertib was administered orally twice daily for 14 days followed by 14 days of rest (28 day cycle).
Gemcitabine at a dose of 1000 mg/m\^2 was administered intravenously once per week for 7 weeks followed by 1 week of rest and then once per week for 3 weeks of every 4 weeks. | 4 |
| Phase 1b: 300 mg Galunisertib + Gemcitabine Cohort 3: 150 mg Galunisertib was administered orally twice daily for 14 days followed by 14 days of rest (28 day cycle).
Gemcitabine at a dose of 1000 mg/m\^2 was administered intravenously once per week for 7 weeks followed by 1 week of rest and then once per week for 3 weeks of every 4 weeks. | 5 |
| Phase 2: 300 mg Galunisertib + Gemcitabine Galunisertib recommended dose (300 mg) determined from phase 1, administered orally twice daily for 14 days followed by 14 days of rest (28 day cycle).
Gemcitabine at a dose of 1000 mg/m\^2 was administered intravenously once per week for 7 weeks followed by 1 week of rest and then once per week for 3 weeks of every 4 weeks. | 103 |
| Phase 2: Placebo + Gemcitabine Placebo administered orally twice daily for 14 days followed 14 days of rest (28 day cycle).
Gemcitabine at a dose of 1000 mg/m\^2 was administered intravenously once per week for 7 weeks followed by 1 week of rest and then once per week for 3 weeks of every 4 weeks. participants may continue until disease progression, unacceptable toxicity, or another withdrawal criterion is met. | 52 |
| Total | 169 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 10 | 2 |
Baseline characteristics
| Characteristic | Phase 1b: 80 mg Galunisertib + Gemcitabine | Phase 1b: 160 mg Galunisertib + Gemcitabine | Phase 1b: 300 mg Galunisertib + Gemcitabine | Phase 2: 300 mg Galunisertib + Gemcitabine | Phase 2: Placebo + Gemcitabine | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 63.2 Years STANDARD_DEVIATION 12.9 | 63.8 Years STANDARD_DEVIATION 9 | 56.6 Years STANDARD_DEVIATION 9.2 | 67.3 Years STANDARD_DEVIATION 8.2 | 66.3 Years STANDARD_DEVIATION 8.9 | 63.5 Years STANDARD_DEVIATION 9.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 4 Participants | 4 Participants | 37 Participants | 18 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 66 Participants | 34 Participants | 100 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 8 Participants | 2 Participants | 10 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 5 Participants | 95 Participants | 50 Participants | 157 Participants |
| Region of Enrollment Belgium | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment France | 0 Participants | 0 Participants | 0 Participants | 21 Participants | 9 Participants | 30 Participants |
| Region of Enrollment Germany | 0 Participants | 0 Participants | 0 Participants | 22 Participants | 14 Participants | 36 Participants |
| Region of Enrollment Italy | 0 Participants | 0 Participants | 0 Participants | 23 Participants | 10 Participants | 33 Participants |
| Region of Enrollment Spain | 0 Participants | 2 Participants | 4 Participants | 26 Participants | 13 Participants | 45 Participants |
| Region of Enrollment United States | 5 Participants | 2 Participants | 1 Participants | 7 Participants | 4 Participants | 19 Participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 3 Participants | 46 Participants | 24 Participants | 76 Participants |
| Sex: Female, Male Male | 5 Participants | 1 Participants | 2 Participants | 57 Participants | 28 Participants | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 4 / 4 | 5 / 5 | 100 / 103 | 49 / 52 |
| serious Total, serious adverse events | 1 / 5 | 1 / 4 | 2 / 5 | 56 / 103 | 26 / 52 |
Outcome results
Primary
Phase 1b: Recommended Phase 2 Dose
The recommended Phase 2 dose was the highest dose where less than 1/3 of participants experienced dose limiting toxicities (DLTs). The recommended dose was determined based on a review of overall toxicity, dose reductions, omissions, and pharmacokinetic information from Phase 1b.
Time frame: Time of first phase 1b dose until time of last phase 1b dose (up to 1 year)
Population: Phase 1b: All participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b Participants | Phase 1b: Recommended Phase 2 Dose | 300 milligrams (mg) |
Primary
Phase 2: Overall Survival (OS)
Overall survival is defined as the time from the date of randomization to the date of death from any cause. For each participant who is not known to have died as of the data-inclusion cut-off date for a particular analysis, overall survival duration was censored for that analysis at the date of last prior contact.
Time frame: Baseline to date of death from any cause (up to 2 years)
Population: All randomized participants who received at least one dose of study drug and had baseline \& at least one post baseline observation. Number of participants censored were Galunisertib + Gemcitabine = 20 and Placebo + Gemcitabine = 4.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b Participants | Phase 2: Overall Survival (OS) | 8.9 Months |
| Phase 2: Placebo + Gemcitabine | Phase 2: Overall Survival (OS) | 7.1 Months |
95% CI: [0.59, 1.085]Bayesian Analysis
Secondary
Phase 1b: Number of Participants With Tumor Response
Response was defined using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Complete Response (CR) was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 millimeter (mm) and normalization of tumor marker level of non-target lesions; Partial Response (PR) was defined as having at least a 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD) was defined as having at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase above nadir; Stable Disease (SD) was defined as small changes that did not meet above criteria.
Time frame: Baseline to end of Phase 1b (up to 1 year)
Population: Phase 1b: All participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1b Participants | Phase 1b: Number of Participants With Tumor Response | Not Assessed (NA) | 1 Participants |
| Phase 1b Participants | Phase 1b: Number of Participants With Tumor Response | Partial Response (PR) | 0 Participants |
| Phase 1b Participants | Phase 1b: Number of Participants With Tumor Response | Progressive Disease (PD) | 3 Participants |
| Phase 1b Participants | Phase 1b: Number of Participants With Tumor Response | Non-Complete Response/Non-Progressive Disease (NC) | 0 Participants |
| Phase 1b Participants | Phase 1b: Number of Participants With Tumor Response | Stable Disease (SD) | 1 Participants |
| Phase 2: Placebo + Gemcitabine | Phase 1b: Number of Participants With Tumor Response | Stable Disease (SD) | 2 Participants |
| Phase 2: Placebo + Gemcitabine | Phase 1b: Number of Participants With Tumor Response | Non-Complete Response/Non-Progressive Disease (NC) | 0 Participants |
| Phase 2: Placebo + Gemcitabine | Phase 1b: Number of Participants With Tumor Response | Progressive Disease (PD) | 1 Participants |
| Phase 2: Placebo + Gemcitabine | Phase 1b: Number of Participants With Tumor Response | Partial Response (PR) | 1 Participants |
| Phase 2: Placebo + Gemcitabine | Phase 1b: Number of Participants With Tumor Response | Not Assessed (NA) | 0 Participants |
| Phase 1b: 300 mg Galunisertib + Gemcitabine | Phase 1b: Number of Participants With Tumor Response | Not Assessed (NA) | 0 Participants |
| Phase 1b: 300 mg Galunisertib + Gemcitabine | Phase 1b: Number of Participants With Tumor Response | Non-Complete Response/Non-Progressive Disease (NC) | 1 Participants |
| Phase 1b: 300 mg Galunisertib + Gemcitabine | Phase 1b: Number of Participants With Tumor Response | Partial Response (PR) | 0 Participants |
| Phase 1b: 300 mg Galunisertib + Gemcitabine | Phase 1b: Number of Participants With Tumor Response | Stable Disease (SD) | 2 Participants |
| Phase 1b: 300 mg Galunisertib + Gemcitabine | Phase 1b: Number of Participants With Tumor Response | Progressive Disease (PD) | 2 Participants |
Secondary
Phase 1b: Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 24 Hours (AUC[0-24], ss) and Time Zero to Infinity (AUC[0-∞], ss)
AUC\[0-24h\] is a combined measure obtained from Day 14 at 0 hour (pre-dose), 0.5, 2,3, 6 hours post dose and morning doses from 24h and 48h to compute. AUC0-infinity will take 48h and extrapolation beyond this in addition to earlier time points to be calculated. All mentioned time points are used to calculate the two AUCs.
Time frame: Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)
Population: Phase 1b: All participants who received at least one dose of study drug and had evaluable PK (pharmacokinetics) data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b Participants | Phase 1b: Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 24 Hours (AUC[0-24], ss) and Time Zero to Infinity (AUC[0-∞], ss) | AUC(0-24) | 2530 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 116 |
| Phase 1b Participants | Phase 1b: Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 24 Hours (AUC[0-24], ss) and Time Zero to Infinity (AUC[0-∞], ss) | AUC(0-∞) | 2740 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 117 |
| Phase 2: Placebo + Gemcitabine | Phase 1b: Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 24 Hours (AUC[0-24], ss) and Time Zero to Infinity (AUC[0-∞], ss) | AUC(0-24) | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Phase 2: Placebo + Gemcitabine | Phase 1b: Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 24 Hours (AUC[0-24], ss) and Time Zero to Infinity (AUC[0-∞], ss) | AUC(0-∞) | NA nanogram*hour per milliliter (ng*h/mL) | — |
| Phase 1b: 300 mg Galunisertib + Gemcitabine | Phase 1b: Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 24 Hours (AUC[0-24], ss) and Time Zero to Infinity (AUC[0-∞], ss) | AUC(0-∞) | 10600 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 10 |
| Phase 1b: 300 mg Galunisertib + Gemcitabine | Phase 1b: Pharmacokinetics: Area Under the Concentration-Time Curve at Steady State From Time Zero to 24 Hours (AUC[0-24], ss) and Time Zero to Infinity (AUC[0-∞], ss) | AUC(0-24) | 9090 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 27 |
Secondary
Phase 1b: Pharmacokinetics: Maximum Plasma Drug Concentration at Steady State (Cmax,ss)
Plasma samples for pharmacokinetic (PK) analysis were obtained on Day 14 at 0 hours (Pre-dose), 0.5, 2, 3, 6 hours post dose and morning doses from 24h and 48h. Cmax takes all time points post dose into account and one value is reported.
Time frame: Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)
Population: Phase 1b: All participants who received at least one dose of study drug and had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b Participants | Phase 1b: Pharmacokinetics: Maximum Plasma Drug Concentration at Steady State (Cmax,ss) | 385 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 101 |
| Phase 2: Placebo + Gemcitabine | Phase 1b: Pharmacokinetics: Maximum Plasma Drug Concentration at Steady State (Cmax,ss) | NA nanogram per milliliter (ng/mL) | — |
| Phase 1b: 300 mg Galunisertib + Gemcitabine | Phase 1b: Pharmacokinetics: Maximum Plasma Drug Concentration at Steady State (Cmax,ss) | 1050 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 39 |
Secondary
Phase 2: Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) at Study Completion
The BPI-SF Pain Severity Subscale was a participant-rated questionnaire that measured the severity of pain. Severity scores could have ranged from 0 (no pain) to 10 (pain as bad as you can imagine) for questions that included assessing average pain in the past 24 hours.
Time frame: Baseline, study treatment completion (up to 1 year)
Population: All randomized participants who received at least 1 dose of study drug and had baseline and a post-baseline measurement for BPI-sf.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b Participants | Phase 2: Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) at Study Completion | 2.54 Units on a scale | Standard Deviation 2.53 |
| Phase 2: Placebo + Gemcitabine | Phase 2: Change From Baseline in Brief Pain Inventory-short Form (BPI-sf) at Study Completion | 1.50 Units on a scale | Standard Deviation 2.12 |
Secondary
Phase 2: Change From Baseline in Carbohydrate Antigen 19.9 (CA19-9) Level at First Study Completion Follow-up
Carbohydrate antigen 19-9 (CA 19-9) is a modified Lewis(a) blood group antigen, and has been used as a tumor marker. The outcome measure is the median, minimum and maximum values from participants who had samples collected at baseline and at follow-up
Time frame: Baseline, study treatment completion after first follow up visit (up to 1 year)
Population: All randomized participants who received at least 1 dose of study drug and had baseline and a post-baseline measurement for CA19-9 level.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b Participants | Phase 2: Change From Baseline in Carbohydrate Antigen 19.9 (CA19-9) Level at First Study Completion Follow-up | 32.7 Units/Milliliter (U/mL) |
| Phase 2: Placebo + Gemcitabine | Phase 2: Change From Baseline in Carbohydrate Antigen 19.9 (CA19-9) Level at First Study Completion Follow-up | -33.3 Units/Milliliter (U/mL) |
Secondary
Phase 2: Percentage Change From Baseline in Tumor Size (CTS)
Change in tumor size is defined as the maximum percent change from baseline in the sum of target lesions. Change was assessed in each participant using radiographic imaging.
Time frame: Baseline, end of Cycle 2 (up to 56 days)
Population: All randomized participants who received at least 1 dose of study drug and had baseline and a post-baseline measurement for change in tumor size.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Phase 1b Participants | Phase 2: Percentage Change From Baseline in Tumor Size (CTS) | Independent Assessor 2 | 1.03 Percent change in tumor size |
| Phase 1b Participants | Phase 2: Percentage Change From Baseline in Tumor Size (CTS) | Independent Assessor 1 | 0.95 Percent change in tumor size |
| Phase 2: Placebo + Gemcitabine | Phase 2: Percentage Change From Baseline in Tumor Size (CTS) | Independent Assessor 1 | 0.92 Percent change in tumor size |
| Phase 2: Placebo + Gemcitabine | Phase 2: Percentage Change From Baseline in Tumor Size (CTS) | Independent Assessor 2 | 0.98 Percent change in tumor size |
Secondary
Phase 2: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR])
Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the independent central review according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100.
Time frame: Baseline to measured progressive disease (up to 2 years)
Population: All randomized participants who received at least 1 dose of study drug and had baseline and a post-baseline measurement for ORR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b Participants | Phase 2: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR]) | 10.6 Percentage of Participants |
| Phase 2: Placebo + Gemcitabine | Phase 2: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate[ORR]) | 3.8 Percentage of Participants |
Secondary
Phase 2: Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24])
AUC\[0-24\] is a combined measure obtained from Day 14 at 0 hour (pre-dose), 0.5, 2,3, 6 hours post dose and morning doses from 24h and 48h to compute.
Time frame: Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)
Population: All randomized participants who received at least 1 dose of study drug with evaluable PK data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phase 1b Participants | Phase 2: Population Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC[0-24]) | 5.56 mg*h/L |
Secondary
Phase 2: Population PK: Maximum Concentration (Cmax) of Galunisertib
Plasma samples for pharmacokinetic (PK) analysis were obtained on Day 14 at 0 hours (Pre-dose), 0.5, 2, 3, 6 hours post dose and morning doses from 24h and 48h. Cmax takes all time points post dose into account and one value is reported.
Time frame: Cycle 1 Days 14 (predose; 0.5, 2, 3, and 6 hours post dose), 24h (Days 15) and 48h (Days 16)
Population: All randomized participants who received at least 1 dose of study drug with evaluable PK data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phase 1b Participants | Phase 2: Population PK: Maximum Concentration (Cmax) of Galunisertib | 904 ng/mL |
Secondary
Phase 2: Progression Free Survival (PFS)
PFS is defined as the date of randomization to the first date of progression of disease or of death from any cause. For each participant who is not known to have died or to have had a progression of disease as of the data-inclusion cut-off date for a particular analysis, PFS will be censored at the date of last prior contact. PFS will be calculated and analyzed twice: (1) including clinical progressions of disease not based on lesion measurements, and (2) excluding clinical progressions. Progression Disease (PD) was defined as having at least a 25% increase in the sum of the longest diameter of target lesions.
Time frame: Baseline to first date of progressive disease or death due to any cause (up to 2 years)
Population: All randomized participants who received at least one dose of study drug and had baseline \& at least one post baseline observation. Number of participants censored were Galunisertib + Gemcitabine = 21 and Placebo + Gemcitabine = 11.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b Participants | Phase 2: Progression Free Survival (PFS) | 4.11 Months |
| Phase 2: Placebo + Gemcitabine | Phase 2: Progression Free Survival (PFS) | 2.86 Months |